rs796053157

Positions:

• chr2-165388692-G-A
• chr2-165388692-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_001040142.2(SCN2A):​c.4886G>A​(p.Arg1629His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.98

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a repeat IV (size 298) in uniprot entity SCN2A_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001040142.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN2A. . Trascript score misZ 8.7114 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 2-165388692-G-A is Pathogenic according to our data. Variant chr2-165388692-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN2A	NM_001040142.2	c.4886G>A	p.Arg1629His	missense_variant	27/27	ENST00000375437.7	NP_001035232.1
SCN2A	NM_001371246.1	c.4886G>A	p.Arg1629His	missense_variant	27/27	ENST00000631182.3	NP_001358175.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN2A	ENST00000375437.7	c.4886G>A	p.Arg1629His	missense_variant	27/27	5	NM_001040142.2	ENSP00000364586	P1
SCN2A	ENST00000631182.3	c.4886G>A	p.Arg1629His	missense_variant	27/27	5	NM_001371246.1	ENSP00000486885

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Developmental and epileptic encephalopathy, 11 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Génétique des Maladies du Développement, Hospices Civils de Lyon	Oct 05, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.4886G>A (p.Arg1629His) missense variant in SCN2A gene has been reported in an individual with neonatal seizures and severe intellectual disability (Wolff et al., 2017). The variant has also been reported in a child with neonatal onset of multifocal seizures and developmental delay (Sandu et al., 2017). The p.Arg1629His variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Arg at position 1629 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor of the fourth homologous domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic/Uncertain Significance. The amino acid change p.Arg1629His in SCN2A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Missense variants at the same residue and in nearby residues have been reported in the Human Gene Mutation Database in individuals with SCN2A-related disorders (Nakamura et al., 2013; Nashabat et al., 2019). For these reasons, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	May 10, 2019	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 27, 2021

The c.4886G>A (p.R1629H) alteration is located in exon 27 (coding exon 26) of the SCN2A gene. This alteration results from a G to A substitution at nucleotide position 4886, causing the arginine (R) at amino acid position 1629 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in multiple unrelated patients with epilepsy (Hamdan, 2017; Wolff, 2017; Kong, 2019). In addition, two other alterations affecting the same amino acid, p.R1629P and p.R1629L, were reported in patients with epilepsy (Nakamura, 2013; Symonds, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Neurology Department, Shenzhen Children's Hospital

Feb 16, 2022

- -

Seizures, benign familial infantile, 3;C3150987:Developmental and epileptic encephalopathy, 11 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 26, 2023

This missense change has been observed in individual(s) with SCN2A-related conditions (PMID: 28379373, 29100083, 30619928, 31054490). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207019). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SCN2A protein function. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1629 of the SCN2A protein (p.Arg1629His). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2018

The R1629H variant in the SCN2A gene has been reported previously as a de novo variant in an individual with neonatal seizures and severe intellectual disability (Wolff et al., 2017). The variant has also been reported in a child with neonatal onset of multifocal seizures and developmental delay, and itwas inherited from this individual's mother who had a history of neonatal seizures (Sandu et al., 2017). The R1629H variant has also been identified at GeneDx as a de novo variant in two unrelatedindividuals with epilepsy. The R1629H variant is not observed in large population cohorts (Lek et al., 2016). The R1629H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution is predicted to be within the transmembrane segment S4 voltage sensor of the fourth homologous domain. In-silicoanalyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants at the same residue and in nearby residues have been reported in the Human Gene Mutation Database in individuals with SCN2A-related disorders (Stenson et al., 2014; Nakamura et al., 2013). Therefore, we interpret R1629H as a pathogenic variant and its presence is consistent with thediagnosis of an SCN2A-related disorder in this individual. -

Epilepsy of infancy with migrating focal seizures Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department of Neurology, Children’s Hospital of Chongqing Medical University

-

- -

Seizures, benign familial infantile, 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Complex neurodevelopmental disorder Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Jul 10, 2019

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2019-07-10 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight and, in one family in multiple siblings. Additional phenotypic information for other sibling(s) might be available from Simons Searchlight. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;T;.;D;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;.;.;.;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;H;.;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.3	D;.;.;.;.;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;.;.;D;D
Sift4G	Uncertain	0.0090	D;.;.;D;.;D;D
Polyphen		0.10	B;D;.;D;B;B;D
Vest4		0.87
MutPred		0.85		Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);.;Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);Loss of MoRF binding (P = 0.0291);
MVP		1.0
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.84
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796053157; hg19: chr2-166245202;